Tyrosine kinase receptors play an important role in tumor angiogenesis, proliferation, migration and infiltration of tumor cells. More than 100 tyrosine kinase inhibitor drugs have been marketed or entered into clinical trial phase successively. These small molecule tyrosine kinase inhibitors (TKIs) play a role in a manner of reversible inhibition, which brings some disadvantages: 1) the selectivity is not good enough, 2) the efficacy is not strong and lasting enough, 3) it is easy to cause drug resistance. Therefore, scientists are encouraged to focus their research on the development of irreversible TKIs.
Irreversible TKIs are typically based on the backbone structure of a reversible TKI, with an electrophilic functional group attached at appropriate position. The electrophilic functional group can form a covalent bond by an electrophilic reaction with a cysteine residue (electron-rich nucleophilic structure) near the ATP-binding domain of tyrosine kinase, thereby irreversibly inhibiting kinase activity. Compared with reversible TKIs, irreversible TKIs have many unique advantages: 1) irreversible TKIs function in a permanent inactivation manner, and this way of inhibiting enzyme activity makes its effect stronger and longer, thereby maintaining the efficacy even if the drug molecule is completely removed from the circulatory system; 2) the development of drug resistance is reduced or avoided due to the absence of ATP competition for binding TKIs to kinase, which reduces the likelihood of mutation of kinase; and 3) the selectivity of the irreversible TKIs is very high due to the electrophilic functional group on the molecular structure of TKIs selectively reacts with a thiol group on a cysteine residue. Based on the above characteristics, the development of irreversible TKIs is gradually becoming a hot spot for research and development.
Fibroblast growth factor receptor (FGFR) is an important member of the tyrosine kinase receptor family. FGFR contains four members, namely FGFR-1, FGFR-2, FGFR-3 and FGFR-4. They are mostly single-chain glycoprotein molecule with molecule mass ranging from 110 kd to 150 kd, comprising an extracellular region, a transmembrane region and an intracellular region. Under normal physiological conditions, FGFR binds to its ligand, fibroblast growth factor (FGF), and results in dimerization and phosphorylation itself, thereby activating downstream signalling pathway, such as the JAK/STAT pathway, the phospholipase C pathway, the phosphatidylinositol-3-kinase PI3K pathway, and the MAPK signalling pathway, which play important roles in tumor growth and angiogenesis. The abnormal high expression of FGFR is closely related to the development of various tumors such as lung cancer, liver cancer, glioma, rhabdomyosarcoma and melanoma.
There are currently no irreversible FGFR inhibitor drugs available, especially the irreversible inhibitors with high selectivity for pan-FGFR.